This invention generally relates to methods for treating tumors, and more particularly methods for treating tumors using borane derivatives both free and liposome encapsulated.
Neutron capture therapy is an attractive method for cancer therapy, specifically the treatment of malignant tumors. The generalized reaction involves capture of a thermalized neutron (usually from a nuclear reactor with special moderators and ports) by an appropriate nucleus having a large neutron capture cross-section. The subsequent decay emits energetic particles (alpha particles) which can kill nearby tumor cells. Since the energetic and cytotoxic alpha particles travel only about one cell diameter in tissue, preferably one may specify the cell type to be destroyed by placing the alpha particle precursors only on or within the tumor cells.
Boron-10 (also designated as 10B), for example, has such an appropriate nucleus and has particularly advantageous properties for this scheme. The boron-10/therinal neutron capture reaction is as follows (* indicating an unstable intermediate state of the boron nucleus):
10B+1nxe2x86x92[11B]*xe2x86x927Li(0.87 Mev.)+4He(1.52 Mev.)
In order for this therapy to be effective, sufficient 10B must be localized in a tumor to generate the required density of particles. This level has been variously estimated to be approximately 10-50 xcexcg10B/gm tumor. Furthermore, the concentration of 10B in normal tissue and blood should be limited and preferably less than the concentration in the tumor in order to minimize damage to healthy cells and blood vessels. H. Hatanaka (1986) Boron-Neutron Capture Therapy for Tumors; Nishimura Co., Ltd. p. 1-16.
Large numbers of boron containing compounds have been tested for their ability to satisfy the above criteria. With few exceptions, all have failed as not enough boron has localized in the tumor and the concentration in the blood has been too high for effective neutron capture therapy. Human clinical trials with Na2B12H11SH in Japan have shown some promise, but only for a limited group of brain tumors. Id. 16-26.
Neutron capture therapy would be greatly expanded in usefulness if a generalized method for delivering high concentrations of 10B to tumors were available. It would further be useful if more 10B collected in tumor than in the blood.
Recently it has become possible to deliver drugs and other compounds selectively to tumors using liposomes of a particular composition structure. See European Patent Application No. 87311040.7 published Jun. 22, 1988; U.S. Pat. No. 5,019,369 to Presant; and xe2x80x9cLiposomes from Biophysics to Therapeuticsxe2x80x9d, M. J. Ostro, Ed., Marcel Dekker, Inc., New York (1987), all of which are incorporated herein by reference.
Incorporation of compounds with higher osmolarity inside the internal space of liposomes than outside, as is necessary for effective neutron capture therapy, depends on incorporating the highest concentration of 10B possible without substantially altering the liposome""s favorable biodistribution characteristics. Thus, the objective of at least 10 xcexcg 10B per gram of tumor tissue can be met (assuming use of greater than 90% 10B enriched material).
Na2B20H18 and its hydroxide derivatives are known. See M. F. Hawthorne, R. L. Pilling, and P. M. Garrett, J. Am. Chem. Soc. 87,4740 (1965). It is known to use boron containing polyphosphonates for the treatment of calcific tumors. See European Patent Application No. 82200784.5 published May 1, 1983. Boronated porphyrin compounds for use in neutron capture therapy are also known. See U.S. Pat. No. 4,959,356 to Miura, U.S. Pat. No. 5,116,980 to Gabel and U.S. Pat. No. 4,466,952 to Hadd.
There is a continuing long felt but unmet need for a method of selectively delivering therapeutic concentrations of 10B to tumors. There is a similar need for 10B compositions and delivery vehicles which can be used in boron neutron capture therapy.
It is an object of the invention to provide compositions and methods for delivering therapeutically useful concentrations of boron containing compounds to tumors for use in neutron capture tumor therapy.
It is a further object to provide borane and liposome encapsulated borane compounds that have the properties of retaining concentrations of said borane compounds inside the liposomes without significant breakage of the liposomes.
It is a further object of the invention to provide a method of cancer therapy through use of both free and liposomal encapsulated borane compounds with the means to deliver at least 10 micrograms 10B per gram of tumor tissue to animal and human tumors, while minimizing the concentration of 10B in the blood.
The above objectives are fulfilled by the present invention. In one aspect of the present invention therapeutically effective borane derivatives having two electron donors on the borane cage are encapsulated within the internal aqueous space of liposomes, and the liposomes thereafter administered to a tumor bearing patient. In another aspect of the present invention, certain free boranes useful for neutron capture therapy have been found to have favorable biodistributions. Preferably both free and liposome encapsulated Na3B20H17NH3 are used in these aspects of the invention. In another aspect of the present invention, therapeutically effective carborane derivatives are embedded within the liposome bilayer for subsequent administration. The resulting liposomes have heightened tumor selectivity and can be used as an encapsulation vehicle for the previously mentioned borane derivatives and for other drugs. In yet another aspect of the present invention novel derivatized boranes are developed for use in boron neutron capture therapy.